Blood pressure gene function revealed
The structure and function of a gene involved in blood pressure regulation has been revealed by a team of British scientists, who hope that their work will lead to the development of new drugs. Their research, which was partly funded by the EU's Sixth Framework Programme, is published online by the journal Nature Medicine. It has been known for some time that Nitric Oxide (NO) plays a key role in regulating blood pressure, and there is evidence that reductions in NO production are linked somehow to the development of cardio-vascular diseases. However, the mechanisms behind this are poorly understood. Our bodies naturally produce two amino acids called Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) which inhibit NO production. People with conditions such as diabetes, renal failure and high blood pressure have higher than normal levels of these molecules, and high concentrations of these molecules in the blood plasma are strongly predicative of heart disease and death. In healthy people, both L-NMMA and ADMA are broken down by a molecule called dimethylarginine dimethylaminohydrolase (DDAH). Yet until now there has been little scientific evidence to clarify the precise roles of DDAH and ADMA in controlling NO levels. In this latest study, researchers investigated what happens in mice whose DDAH levels are lowered. To do this they created mice in which one copy of the DDAH1 gene was defective (mice in which both copies were defective died before birth). The researchers also developed a molecule which blocks the effect of DDAH, and gave this to normal mice. Both sets of mice went on to develop hypertension, confirming DDAH's role in regulating blood pressure. In both cases, reducing DDAH activity, either by deleting the gene or blocking the molecule, lead to levels of ADMA similar to those found in patients with multiple cardiovascular risk factors. Cultures of the arterial cells of the mice with a defective DDAH gene also revealed that they produced lower levels of NO than cells from healthy mice. 'These genetic and chemical approaches to disrupt DDAH showed remarkably consistent results, and provide compelling evidence that loss of DDAH function increases the concentration of ADMA and thereby disrupts vascular NO signalling,' said Dr James Leiper of University College London's Department of Medicine, who led the research. 'Genes and their pathways are crucial to our understanding of cardiovascular disease. It could help us to establish if genetic variation predisposes certain people to these diseases or whether environmental factors exert some of their effects through modulation of DDAH activity.' The scientists also investigated the potential of using DDAH inhibitors as drugs for certain medical conditions, including those where the problem is caused by too much NO. 'This pathway could be harnessed therapeutically to limit production of NO in certain situations where too much nitric oxide is a bad thing; for example hypotension and septic shock,' explained Dr Leiper. 'These are some of the biggest problems in intensive care medicine and there is a huge unmet need for drug treatments.'